James Briscoe
@jamesbriscoe.bsky.social
Developmental Biologist working at the Francis Crick Institute. Neural tube, morphogens, and gene regulatory networks. Editor-in-chief, Development.
London · briscoelab.org
London · briscoelab.org
I do miss the view from my lab on the top floor, but not the rain that came through the window frames if the wind was in the wrong direction.
September 4, 2025 at 4:22 PM
I do miss the view from my lab on the top floor, but not the rain that came through the window frames if the wind was in the wrong direction.
Key finding #3: Dynamic xpts revealed progenitor identity depends on both concentration & duration of Shh
More ventral markers (Nkx2.2) appear later but domain sizes remain constant
This suggests progressive fate assignment reflects gene regulatory dynamics, not gradient dynamics
More ventral markers (Nkx2.2) appear later but domain sizes remain constant
This suggests progressive fate assignment reflects gene regulatory dynamics, not gradient dynamics
August 26, 2025 at 8:28 AM
Key finding #3: Dynamic xpts revealed progenitor identity depends on both concentration & duration of Shh
More ventral markers (Nkx2.2) appear later but domain sizes remain constant
This suggests progressive fate assignment reflects gene regulatory dynamics, not gradient dynamics
More ventral markers (Nkx2.2) appear later but domain sizes remain constant
This suggests progressive fate assignment reflects gene regulatory dynamics, not gradient dynamics
Similarly, the Shh interacting protein Scube2 increased Shh range by ~50%, confirming its role as a "gradient expander" in mammalian systems (previously shown in zebrafish)
The system provides a quantitative readout for morphogen modulator activity
The system provides a quantitative readout for morphogen modulator activity
August 26, 2025 at 8:28 AM
Similarly, the Shh interacting protein Scube2 increased Shh range by ~50%, confirming its role as a "gradient expander" in mammalian systems (previously shown in zebrafish)
The system provides a quantitative readout for morphogen modulator activity
The system provides a quantitative readout for morphogen modulator activity
Key finding #2: Cholesterol-modified Shh showed normal patterning, while non-cholesterol modified Shh (NShh) extended signalling range 3-fold
Membrane-tethered Shh-CD4 abolished long-range signalling
Membrane-tethered Shh-CD4 abolished long-range signalling
August 26, 2025 at 8:28 AM
Key finding #2: Cholesterol-modified Shh showed normal patterning, while non-cholesterol modified Shh (NShh) extended signalling range 3-fold
Membrane-tethered Shh-CD4 abolished long-range signalling
Membrane-tethered Shh-CD4 abolished long-range signalling
Key finding #1: Shh has an extracellular half-life ~1h. Turnover much faster than downstream gene expression dynamics, indicating morphogen gradient is continually renewed during patterning
Suggests Shh's effective diffusion rate: ~0.125 μm²/s, remarkably similar to Dpp/Wingless in Drosophila
Suggests Shh's effective diffusion rate: ~0.125 μm²/s, remarkably similar to Dpp/Wingless in Drosophila
August 26, 2025 at 8:28 AM
Key finding #1: Shh has an extracellular half-life ~1h. Turnover much faster than downstream gene expression dynamics, indicating morphogen gradient is continually renewed during patterning
Suggests Shh's effective diffusion rate: ~0.125 μm²/s, remarkably similar to Dpp/Wingless in Drosophila
Suggests Shh's effective diffusion rate: ~0.125 μm²/s, remarkably similar to Dpp/Wingless in Drosophila
We applied DD-GAVPO to control Sonic hedgehog (Shh) production in a stem cell model of neural tube development
Spatially restricted light illumination recreated long-range Shh gradients that faithfully recapitulated neural tube patterning
Spatially restricted light illumination recreated long-range Shh gradients that faithfully recapitulated neural tube patterning
August 26, 2025 at 8:28 AM
We applied DD-GAVPO to control Sonic hedgehog (Shh) production in a stem cell model of neural tube development
Spatially restricted light illumination recreated long-range Shh gradients that faithfully recapitulated neural tube patterning
Spatially restricted light illumination recreated long-range Shh gradients that faithfully recapitulated neural tube patterning
The dual-control system exhibits minimal leakiness while allowing robust gene induction
By titrating Shld-1 concentration, we can precisely tune activation levels - something challenging to achieve with light alone
It's a dimmer switch, not just a toggle
By titrating Shld-1 concentration, we can precisely tune activation levels - something challenging to achieve with light alone
It's a dimmer switch, not just a toggle
August 26, 2025 at 8:28 AM
The dual-control system exhibits minimal leakiness while allowing robust gene induction
By titrating Shld-1 concentration, we can precisely tune activation levels - something challenging to achieve with light alone
It's a dimmer switch, not just a toggle
By titrating Shld-1 concentration, we can precisely tune activation levels - something challenging to achieve with light alone
It's a dimmer switch, not just a toggle
The challenge: Most existing optogenetic systems suffer from either weak activation OR leaky expression in the dark
To get around this we fused the light-responsive transcription factor GAVPO to a small-molecule responsive degron domain (DD-GAVPO)
Best of both worlds: chemo-optogenetics
To get around this we fused the light-responsive transcription factor GAVPO to a small-molecule responsive degron domain (DD-GAVPO)
Best of both worlds: chemo-optogenetics
August 26, 2025 at 8:28 AM
The challenge: Most existing optogenetic systems suffer from either weak activation OR leaky expression in the dark
To get around this we fused the light-responsive transcription factor GAVPO to a small-molecule responsive degron domain (DD-GAVPO)
Best of both worlds: chemo-optogenetics
To get around this we fused the light-responsive transcription factor GAVPO to a small-molecule responsive degron domain (DD-GAVPO)
Best of both worlds: chemo-optogenetics
Cross-Species Validation: Applying DLA to human neural organoids revealed conserved decision-making principles between mouse & human
The mathematical structure underlying cell fate decisions appear to be fundamental features of vertebrate neural tube development
The mathematical structure underlying cell fate decisions appear to be fundamental features of vertebrate neural tube development
May 29, 2025 at 12:08 PM
Cross-Species Validation: Applying DLA to human neural organoids revealed conserved decision-making principles between mouse & human
The mathematical structure underlying cell fate decisions appear to be fundamental features of vertebrate neural tube development
The mathematical structure underlying cell fate decisions appear to be fundamental features of vertebrate neural tube development
Predictive Power: The model successfully predicts cellular responses to signalling conditions not seen before
When we tested new patterns of Sonic Hedgehog signalling experimentally, the predictions matched xpts
This is true predictive biology, not just curve fitting
When we tested new patterns of Sonic Hedgehog signalling experimentally, the predictions matched xpts
This is true predictive biology, not just curve fitting
May 29, 2025 at 12:08 PM
Predictive Power: The model successfully predicts cellular responses to signalling conditions not seen before
When we tested new patterns of Sonic Hedgehog signalling experimentally, the predictions matched xpts
This is true predictive biology, not just curve fitting
When we tested new patterns of Sonic Hedgehog signalling experimentally, the predictions matched xpts
This is true predictive biology, not just curve fitting
Surprising Finding: Studying neural tube differentiation, we discovered an unexpected circular topology
Cells that initially diverge into different lineages can converge through multiple routes to the same fate
This challenges the traditional "branching tree" view of development
Cells that initially diverge into different lineages can converge through multiple routes to the same fate
This challenges the traditional "branching tree" view of development
May 29, 2025 at 12:08 PM
Surprising Finding: Studying neural tube differentiation, we discovered an unexpected circular topology
Cells that initially diverge into different lineages can converge through multiple routes to the same fate
This challenges the traditional "branching tree" view of development
Cells that initially diverge into different lineages can converge through multiple routes to the same fate
This challenges the traditional "branching tree" view of development
Classifying Decisions: We identified three types of cell fate decisions, each governed by distinct dynamical bifurcations:
• Direct transitions (fold bifurcations)
• Binary flip decisions
• Binary choice decisions
These mathematical structures explain how signalling controls cell fate allocation
• Direct transitions (fold bifurcations)
• Binary flip decisions
• Binary choice decisions
These mathematical structures explain how signalling controls cell fate allocation
May 29, 2025 at 12:08 PM
Classifying Decisions: We identified three types of cell fate decisions, each governed by distinct dynamical bifurcations:
• Direct transitions (fold bifurcations)
• Binary flip decisions
• Binary choice decisions
These mathematical structures explain how signalling controls cell fate allocation
• Direct transitions (fold bifurcations)
• Binary flip decisions
• Binary choice decisions
These mathematical structures explain how signalling controls cell fate allocation
Key Innovation: Getting beyond descriptive trajectories. DLA generates a geometric dynamical model—a Waddington landscape—that provides mechanistic insights without needing every molecular detail
It bridges microscopic gene expression to macroscopic cell behaviour
It bridges microscopic gene expression to macroscopic cell behaviour
May 29, 2025 at 12:08 PM
Key Innovation: Getting beyond descriptive trajectories. DLA generates a geometric dynamical model—a Waddington landscape—that provides mechanistic insights without needing every molecular detail
It bridges microscopic gene expression to macroscopic cell behaviour
It bridges microscopic gene expression to macroscopic cell behaviour
Solution: Dynamic Landscape Analysis (DLA) - a framework rooted in dynamical systems
• Identifies stable cell states as "attractor clusters"
• Maps transition pathways between states
• Builds predictive mathematical models
• Identifies stable cell states as "attractor clusters"
• Maps transition pathways between states
• Builds predictive mathematical models
May 29, 2025 at 12:08 PM
Solution: Dynamic Landscape Analysis (DLA) - a framework rooted in dynamical systems
• Identifies stable cell states as "attractor clusters"
• Maps transition pathways between states
• Builds predictive mathematical models
• Identifies stable cell states as "attractor clusters"
• Maps transition pathways between states
• Builds predictive mathematical models
The Problem: While scRNAseq has revolutionised how we see cellular heterogeneity, we've lacked principled methods to transform these high-dimensional snapshots of gene expression into predictive models that explain HOW cells make decisions
Most approaches describe what we see, not how it happens
Most approaches describe what we see, not how it happens
May 29, 2025 at 12:08 PM
The Problem: While scRNAseq has revolutionised how we see cellular heterogeneity, we've lacked principled methods to transform these high-dimensional snapshots of gene expression into predictive models that explain HOW cells make decisions
Most approaches describe what we see, not how it happens
Most approaches describe what we see, not how it happens
Always a pleasure to visit @mblscience.bsky.social
Looking forward to a few days at #GERN2025
www.mbl.edu/education/ad...
Looking forward to a few days at #GERN2025
www.mbl.edu/education/ad...
April 14, 2025 at 11:26 AM
Always a pleasure to visit @mblscience.bsky.social
Looking forward to a few days at #GERN2025
www.mbl.edu/education/ad...
Looking forward to a few days at #GERN2025
www.mbl.edu/education/ad...
Congratulations to Rory Maizels delivering the @bsdb.bsky.social Beddington Medal lecture at #Biologists100
March 27, 2025 at 4:51 PM
Congratulations to Rory Maizels delivering the @bsdb.bsky.social Beddington Medal lecture at #Biologists100
Always a pleasure seeing previous lab members present their own lab's work
The wonderful Vanessa Ribes discussing recent work on txn regulation by Pax3/7 in neural progenitors #biologists100
www.biorxiv.org/content/10.1...
The wonderful Vanessa Ribes discussing recent work on txn regulation by Pax3/7 in neural progenitors #biologists100
www.biorxiv.org/content/10.1...
March 27, 2025 at 12:10 PM
Always a pleasure seeing previous lab members present their own lab's work
The wonderful Vanessa Ribes discussing recent work on txn regulation by Pax3/7 in neural progenitors #biologists100
www.biorxiv.org/content/10.1...
The wonderful Vanessa Ribes discussing recent work on txn regulation by Pax3/7 in neural progenitors #biologists100
www.biorxiv.org/content/10.1...
Overall, the study establishes a CRISPR screening approach for studying developmental processes in chick embryos
And reveals how transcriptional elongation control via MLLT3/SEC helps coordinate rapid cell fate transitions during development
And reveals how transcriptional elongation control via MLLT3/SEC helps coordinate rapid cell fate transitions during development
February 13, 2025 at 7:50 AM
Overall, the study establishes a CRISPR screening approach for studying developmental processes in chick embryos
And reveals how transcriptional elongation control via MLLT3/SEC helps coordinate rapid cell fate transitions during development
And reveals how transcriptional elongation control via MLLT3/SEC helps coordinate rapid cell fate transitions during development
MLLT3 works through RARα: Mutant RARα lacking the MLLT3 binding domain phenocopied MLLT3 knockout effects on neural progenitors
February 13, 2025 at 7:50 AM
MLLT3 works through RARα: Mutant RARα lacking the MLLT3 binding domain phenocopied MLLT3 knockout effects on neural progenitors
MLLT3 knockout affected expression of RA responsive genes and WNT/PCP pathway components
This positions MLLT3 as a link between NMP maintenance and neural differentiation
This positions MLLT3 as a link between NMP maintenance and neural differentiation
February 13, 2025 at 7:50 AM
MLLT3 knockout affected expression of RA responsive genes and WNT/PCP pathway components
This positions MLLT3 as a link between NMP maintenance and neural differentiation
This positions MLLT3 as a link between NMP maintenance and neural differentiation
We found MLLT3 perturbation disrupted neural tube morphology and reduced neural fate acquisition
Suggests MLLT3 plays a previously unknown role in neural specification
Suggests MLLT3 plays a previously unknown role in neural specification
February 13, 2025 at 7:50 AM
We found MLLT3 perturbation disrupted neural tube morphology and reduced neural fate acquisition
Suggests MLLT3 plays a previously unknown role in neural specification
Suggests MLLT3 plays a previously unknown role in neural specification
Analysis of guide enrichment/depletion across cell populations revealed distinct phenotypic clusters
FGF and RAR knockouts accumulated cells in CLE, consistent with their roles in differentiation
FGF and RAR knockouts accumulated cells in CLE, consistent with their roles in differentiation
February 13, 2025 at 7:50 AM
Analysis of guide enrichment/depletion across cell populations revealed distinct phenotypic clusters
FGF and RAR knockouts accumulated cells in CLE, consistent with their roles in differentiation
FGF and RAR knockouts accumulated cells in CLE, consistent with their roles in differentiation
We validated the CRISPR system using OLIG2 knockouts in neural tube
Then performed a screen targeting 25 genes with 4 guides each (102 total guides including controls) in the CLE
Then performed a screen targeting 25 genes with 4 guides each (102 total guides including controls) in the CLE
February 13, 2025 at 7:50 AM
We validated the CRISPR system using OLIG2 knockouts in neural tube
Then performed a screen targeting 25 genes with 4 guides each (102 total guides including controls) in the CLE
Then performed a screen targeting 25 genes with 4 guides each (102 total guides including controls) in the CLE
We developed a multiplexed CRISPR in vivo screening strategy (aka Perturb-seq) targeting genes expressed in the CLE and neural tube
Key refinement: incorporating capture sequences into gRNAs to enable single-cell RNA-seq tracking of perturbations
Key refinement: incorporating capture sequences into gRNAs to enable single-cell RNA-seq tracking of perturbations
February 13, 2025 at 7:50 AM
We developed a multiplexed CRISPR in vivo screening strategy (aka Perturb-seq) targeting genes expressed in the CLE and neural tube
Key refinement: incorporating capture sequences into gRNAs to enable single-cell RNA-seq tracking of perturbations
Key refinement: incorporating capture sequences into gRNAs to enable single-cell RNA-seq tracking of perturbations